Few studies have investigated the hemodynamic mechanism whereby primary hyperaldosteronism causes hypertension. The traditional view holds that hyperaldosteronism initiates hypertension by amplifying salt-dependent increases in cardiac output (CO) by promoting increases in sodium retention and blood volume. Systemic vascular resistance (SVR) is said to increase only as a secondary consequence of the increased CO and blood pressure. Recently, we investigated the primary hemodynamic mechanism whereby hyperaldosteronism promotes salt sensitivity and initiation of salt-dependent hypertension. In unilaterally nephrectomized male Sprague-Dawley rats given infusions of aldosterone or vehicle, we found that aldosterone promoted salt sensitivity and initiation of salt-dependent hypertension by amplifying salt-induced increases in SVR while decreasing CO. In addition, we validated mathematical models of human integrative physiology, derived from Guyton's classic 1972 model - Quantitative Cardiovascular Physiology-2005 and HumMod-3.0.4. Neither model accurately predicted the usual changes in sodium balance, CO, and SVR that normally occur in response to clinically realistic increases in salt intake. These results demonstrate significant limitations with the hypotheses inherent in the Guyton models. Together these findings challenge the traditional view of the hemodynamic mechanisms that cause salt-sensitive hypertension in primary aldosteronism. Key words: Aldosterone, Blood pressure, Salt, Sodium, Rat.

• MeSH
• Aldosterone blood   metabolism   MeSH
• Hemodynamics * drug effects   MeSH
• Hyperaldosteronism * physiopathology   metabolism   MeSH
• Hypertension * physiopathology   etiology   MeSH
• Blood Pressure drug effects   physiology   MeSH
• Rats MeSH
• Sodium Chloride, Dietary * adverse effects   MeSH
• Models, Cardiovascular MeSH
• Disease Models, Animal * MeSH
• Rats, Sprague-Dawley * MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Aldosterone MeSH
• Sodium Chloride, Dietary * MeSH

High-salt diets are a major cause of hypertension and cardiovascular (CV) disease. Many governments are interested in using food salt reduction programs to reduce the risk for salt-induced increases in blood pressure and CV events. It is assumed that reducing the salt concentration of processed foods will substantially reduce mean salt intake in the general population. However, contrary to expectations, reducing the sodium density of nearly all foods consumed in England by 21% had little or no effect on salt intake in the general population. This may be due to the fact that in England, as in other countries including the U.S.A., mean salt intake is already close to the lower normal physiologic limit for mean salt intake of free-living populations. Thus, mechanism-based strategies for preventing salt-induced increases in blood pressure that do not solely depend on reducing salt intake merit attention. It is now recognized that the initiation of salt-induced increases in blood pressure often involves a combination of normal increases in sodium balance, blood volume and cardiac output together with abnormal vascular resistance responses to increased salt intake. Therefore, preventing either the normal increases in sodium balance and cardiac output, or the abnormal vascular resistance responses to salt, can prevent salt-induced increases in blood pressure. Suboptimal nutrient intake is a common cause of the hemodynamic disturbances mediating salt-induced hypertension. Accordingly, efforts to identify and correct the nutrient deficiencies that promote salt sensitivity hold promise for decreasing population risk of salt-induced hypertension without requiring reductions in salt intake.

• Keywords
• blood pressure, hypertension, nitrate, salt, sodium, sodium chloride,
• MeSH
• Hypertension * chemically induced   prevention & control   MeSH
• Cardiovascular Diseases * MeSH
• Blood Pressure MeSH
• Sodium Chloride, Dietary adverse effects   MeSH
• Humans MeSH
• Sodium MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Sodium Chloride, Dietary MeSH
• Sodium MeSH

Recent studies in humans and rats suggested that increased Na+ storage in the skin without parallel water retention may predispose to salt-sensitive hypertension. In the current studies, we compared tissue Na+ storage in salt sensitive spontaneously hypertensive rats (SHR) versus salt resistant normotensive Brown Norway (BN-Lx) rats. After salt loading (10 days drinking 1% NaCl solution), the SHR showed significant parallel increase in Na+-to-water as well as (Na++K+)-to-water ratios suggesting increased storage of osmotically inactive Na+ in the skin while no significant changes in skin electrolyte concentrations were observed in BN-Lx rats. SHR rats after salt treatment exhibited a nonsignificant decrease in skin blood capillary number (rarefaction) while BN-Lx rats showed significantly increased skin blood capillary density. Analysis of dermal gene expression profiles in BN-Lx rats after salt treatment showed significant up-regulation of genes involved in angiogenesis and proliferation of endothelial cells contrary to the SHR. Since the skin harbors most of the body's resistance vessels it is possible that blood capillary rarefaction may lead to increased peripheral resistance and salt sensitivity in the SHR.

• Keywords
• blood pressure, capillary rarefaction, gene expression, salt, salt-sensitive hypertension, skin, sodium, spontaneously hypertensive rat,
• Publication type
• Journal Article MeSH

On average, black individuals are widely believed to be more sensitive than white individuals to blood pressure (BP) effects of changes in salt intake. However, few studies have directly compared the BP effects of changing salt intake in black versus white individuals. In this narrative review, we analyze those studies and note that when potassium intake substantially exceeds the recently recommended US dietary goal of 87 mmol/day, black adults do not appear more sensitive than white adults to BP effects of short-term or long-term increases in salt intake (from an intake ≤50 mmol/day up to 150 mmol/day or more). However, with lower potassium intakes, racial differences in salt sensitivity are observed. Mechanistic studies suggest that racial differences in salt sensitivity are related to differences in vascular resistance responses to changes in salt intake mediated by vasodilator and vasoconstrictor pathways. With respect to cause and prevention of racial disparities in salt sensitivity, it is noteworthy that 1) on average, black individuals consume less potassium than white individuals and 2) consuming supplemental potassium bicarbonate, or potassium rich foods can prevent racial disparities in salt sensitivity. However, the new US dietary guidelines reduced the dietary potassium goal well below the amount associated with preventing racial disparities in salt sensitivity. These observations should motivate research on the impact of the new dietary potassium guidelines on racial disparities in salt sensitivity, the risks and benefits of potassium-containing salt substitutes or supplements, and methods for increasing consumption of foods rich in nutrients that protect against salt-induced hypertension.

• Keywords
• hypertension, nitrate, race, salt-sensitive, sodium,
• MeSH
• White People MeSH
• Black People MeSH
• Potassium, Dietary * MeSH
• Hypertension physiopathology   MeSH
• Blood Pressure physiology   MeSH
• Humans MeSH
• Risk Factors MeSH
• Sodium, Dietary * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Potassium, Dietary * MeSH
• Sodium, Dietary * MeSH

To reduce the risk of salt-induced hypertension, medical authorities have emphasized dietary guidelines promoting high intakes of potassium and low intakes of salt that provide molar ratios of potassium to salt of ≥1:1. However, during the past several decades, relatively few people have changed their eating habits sufficiently to reach the recommended dietary goals for salt and potassium. Thus, new strategies that reduce the risk of salt-induced hypertension without requiring major changes in dietary habits would be of considerable medical interest. In the current studies in a widely used model of salt-induced hypertension, the Dahl salt-sensitive rat, we found that supplemental dietary sodium nitrate confers substantial protection from initiation of salt-induced hypertension when the molar ratio of added nitrate to added salt is only ≈1:170. Provision of a low molar ratio of added nitrate to added salt of ≈1:110 by supplementing the diet with beetroot also conferred substantial protection against salt-induced increases in blood pressure. The results suggest that on a molar basis and a weight basis, dietary nitrate may be ≈100× more potent than dietary potassium with respect to providing substantial resistance to the pressor effects of increased salt intake. Given that leafy green and root vegetables contain large amounts of inorganic nitrate, these findings raise the possibility that fortification of salty food products with small amounts of a nitrate-rich vegetable concentrate may provide a simple method for reducing risk for salt-induced hypertension.

• Keywords
• diet, hypertension, nitric oxide, rats, sodium,
• MeSH
• Beta vulgaris * MeSH
• Sodium Chloride toxicity   MeSH
• Diet methods   MeSH
• Nitrates administration & dosage   MeSH
• Hypertension chemically induced   physiopathology   prevention & control   MeSH
• Blood Pressure physiology   MeSH
• Rats MeSH
• Disease Models, Animal MeSH
• Rats, Inbred Dahl MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Sodium Chloride MeSH
• Nitrates MeSH

Recently, mathematical models of human integrative physiology, derived from Guyton's classic 1972 model of the circulation, have been used to investigate potential mechanistic abnormalities mediating salt sensitivity and salt-induced hypertension. We performed validation testing of 2 of the most evolved derivatives of Guyton's 1972 model, Quantitative Cardiovascular Physiology-2005 and HumMod-3.0.4, to determine whether the models accurately predict sodium balance and hemodynamic responses of normal subjects to increases in salt intake within the real-life range of salt intake in humans. Neither model, nor the 1972 Guyton model, accurately predicts the usual changes in sodium balance, cardiac output, and systemic vascular resistance that normally occur in response to clinically realistic increases in salt intake. Furthermore, although both contemporary models are extensions of the 1972 Guyton model, testing revealed major inconsistencies between model predictions with respect to sodium balance and hemodynamic responses of normal subjects to short-term and long-term salt loading. These results demonstrate significant limitations with the hypotheses inherent in the Guyton models regarding the usual regulation of sodium balance, cardiac output, and vascular resistance in response to increased salt intake in normal salt-resistant humans. Accurate understanding of the normal responses to salt loading is a prerequisite for accurately establishing abnormal responses to salt loading. Accordingly, the present results raise concerns about the interpretation of studies of salt sensitivity with the various Guyton models. These findings indicate a need for continuing development of alternative models that incorporate mechanistic concepts of blood pressure regulation fundamentally different from those in the 1972 Guyton model and its contemporary derivatives.

• Keywords
• blood pressure, cardiac output, hypertension, sodium chloride, vascular resistance,
• MeSH
• Hemodynamics physiology   MeSH
• Hypertension etiology   physiopathology   MeSH
• Blood Pressure physiology   MeSH
• Sodium Chloride, Dietary * MeSH
• Humans MeSH
• Cardiac Output physiology   MeSH
• Models, Cardiovascular * MeSH
• Computer Simulation * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Sodium Chloride, Dietary * MeSH

High salt intake is one of the major dietary determinants of hypertension and cardiovascular disease in Japan and throughout the world. Although dietary salt restriction may be of clinical benefit in salt-sensitive individuals, many individuals may not wish, or be able to, reduce their intake of salt. Thus, identification of functional foods that can help protect against mechanistic abnormalities mediating salt-induced hypertension is an issue of considerable medical and scientific interest. According to the "vasodysfunction" theory of salt-induced hypertension, the hemodynamic abnormality initiating salt-induced increases in blood pressure usually involves subnormal vasodilation and abnormally increased vascular resistance in response to increased salt intake. Because disturbances in nitric oxide activity can contribute to subnormal vasodilator responses to increased salt intake that often mediate blood pressure salt sensitivity, increased intake of functional foods that support nitric oxide activity may help to reduce the risk for salt-induced hypertension. Mounting evidence indicates that increased consumption of traditional Japanese vegetables and other vegetables with high nitrate content such as table beets and kale can promote the formation of nitric oxide through an endothelial independent pathway that involves reduction of dietary nitrate to nitrite and nitric oxide. In addition, recent studies in animal models have demonstrated that modest increases in nitrate intake can protect against the initiation of salt-induced hypertension. These observations are: (1) consistent with the view that increased intake of many traditional Japanese vegetables and other nitrate rich vegetables, and of functional foods derived from such vegetables, may help maintain healthy blood pressure despite a high salt diet; (2) support government recommendations to increase vegetable intake in the Japanese population.

• Keywords
• Hypertension, Nitrate, Salt, Salt sensitivity, Sodium,
• MeSH
• Functional Food * MeSH
• Hypertension prevention & control   MeSH
• Cardiovascular Diseases prevention & control   MeSH
• Sodium Chloride, Dietary adverse effects   MeSH
• Humans MeSH
• Nitric Oxide metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Geographicals
• Japan MeSH
• Names of Substances
• Sodium Chloride, Dietary MeSH
• Nitric Oxide MeSH

• Keywords
• hypertension, salt intake, salt sensitivity hypertension, salt‐sensitive, sodium,
• MeSH
• Hypertension diagnosis   etiology   physiopathology   MeSH
• Blood Pressure drug effects   physiology   MeSH
• Sodium Chloride, Dietary adverse effects   MeSH
• Humans MeSH
• Risk Factors MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Sodium Chloride, Dietary MeSH